FIP1L1-PDGFRalpha imposes eosinophil lineage commitment on hematopoietic stem/progenitor cells

J Biol Chem. 2009 Mar 20;284(12):7719-32. doi: 10.1074/jbc.M807489200. Epub 2009 Jan 14.


Although leukemogenic tyrosine kinases (LTKs) activate a common set of downstream molecules, the phenotypes of leukemia caused by LTKs are rather distinct. Here we report the molecular mechanism underlying the development of hypereosinophilic syndrome/chronic eosinophilic leukemia by FIP1L1-PDGFRalpha. When introduced into c-Kit(high)Sca-1(+)Lineage(-) cells, FIP1L1-PDGFRalpha conferred cytokine-independent growth on these cells and enhanced their self-renewal, whereas it did not immortalize common myeloid progenitors in in vitro replating assays and transplantation assays. Importantly, FIP1L1-PDGFRalpha but not TEL-PDGFRbeta enhanced the development of Gr-1(+)IL-5Ralpha(+) eosinophil progenitors from c-Kit(high)Sca-1(+)Lineage(-) cells. FIP1L1-PDGFRalpha also promoted eosinophil development from common myeloid progenitors. Furthermore, when expressed in megakaryocyte/erythrocyte progenitors and common lymphoid progenitors, FIP1L1-PDGFRalpha not only inhibited differentiation toward erythroid cells, megakaryocytes, and B-lymphocytes but aberrantly developed eosinophil progenitors from megakaryocyte/erythrocyte progenitors and common lymphoid progenitors. As for the mechanism of FIP1L1-PDGFRalpha-induced eosinophil development, FIP1L1-PDGFRalpha was found to more intensely activate MEK1/2 and p38(MAPK) than TEL-PDGFRbeta. In addition, a MEK1/2 inhibitor and a p38(MAPK) inhibitor suppressed FIP1L1-PDGFRalpha-promoted eosinophil development. Also, reverse transcription-PCR analysis revealed that FIP1L1-PDGFRalpha augmented the expression of C/EBPalpha, GATA-1, and GATA-2, whereas it hardly affected PU.1 expression. In addition, short hairpin RNAs against C/EBPalpha and GATA-2 and GATA-3KRR, which can act as a dominant-negative form over all GATA members, inhibited FIP1L1-PDGFRalpha-induced eosinophil development. Furthermore, FIP1L1-PDGFRalpha and its downstream Ras inhibited PU.1 activity in luciferase assays. Together, these results indicate that FIP1L1-PDGFRalpha enhances eosinophil development by modifying the expression and activity of lineage-specific transcription factors through Ras/MEK and p38(MAPK) cascades.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CCAAT-Enhancer-Binding Protein-alpha / genetics
  • CCAAT-Enhancer-Binding Protein-alpha / metabolism
  • Cell Differentiation*
  • Cells, Cultured
  • Chronic Disease
  • Cytokines / genetics
  • Cytokines / metabolism
  • Eosinophils / enzymology*
  • Eosinophils / pathology
  • GATA1 Transcription Factor / genetics
  • GATA1 Transcription Factor / metabolism
  • GATA2 Transcription Factor / genetics
  • GATA2 Transcription Factor / metabolism
  • Hematopoietic Stem Cell Transplantation
  • Hematopoietic Stem Cells
  • Humans
  • Hypereosinophilic Syndrome / enzymology*
  • Hypereosinophilic Syndrome / genetics
  • Hypereosinophilic Syndrome / metabolism
  • Hypereosinophilic Syndrome / pathology
  • MAP Kinase Kinase 1 / genetics
  • MAP Kinase Kinase 1 / metabolism
  • MAP Kinase Kinase 2 / genetics
  • MAP Kinase Kinase 2 / metabolism
  • MAP Kinase Signaling System*
  • Mice
  • Oncogene Proteins, Fusion / genetics
  • Oncogene Proteins, Fusion / metabolism*
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins / metabolism
  • Receptor, Platelet-Derived Growth Factor alpha / genetics
  • Receptor, Platelet-Derived Growth Factor alpha / metabolism*
  • Trans-Activators / genetics
  • Trans-Activators / metabolism
  • Transcription, Genetic / genetics
  • Transplantation, Homologous
  • mRNA Cleavage and Polyadenylation Factors / genetics
  • mRNA Cleavage and Polyadenylation Factors / metabolism*
  • p38 Mitogen-Activated Protein Kinases / genetics
  • p38 Mitogen-Activated Protein Kinases / metabolism


  • CCAAT-Enhancer-Binding Protein-alpha
  • Cytokines
  • GATA1 Transcription Factor
  • GATA2 Transcription Factor
  • Gata1 protein, mouse
  • Gata2 protein, mouse
  • Oncogene Proteins, Fusion
  • Proto-Oncogene Proteins
  • Trans-Activators
  • mRNA Cleavage and Polyadenylation Factors
  • proto-oncogene protein Spi-1
  • MAP2K2 protein, human
  • FIP1L1-PDGFRA fusion protein, human
  • Receptor, Platelet-Derived Growth Factor alpha
  • p38 Mitogen-Activated Protein Kinases
  • MAP Kinase Kinase 1
  • MAP Kinase Kinase 2
  • MAP2K1 protein, human
  • Map2k1 protein, mouse
  • Map2k2 protein, mouse